Srecko Nedeljkovic

The Seven Countries Study : 2,289 deaths in 15 years

Among 11,579 men ages 40-59 without evidence of cardiovascular disease, 2,289 died in 15 years, 618 from coronary heart disease. The 15 cohorts in seven countries (four regions) differed in all-causes death rate, mainly reflecting great differences in coronary mortality. Among characteristics of entry, only mean blood pressure helped to explain cohort differences in all-causes death rate. Three-quarters of the variance in coronary death rate was accounted for by differences in mean serum cholesterol and blood pressure of the cohorts. The mortality risk for individuals was examined in each of the regions. For coronary death, age, serum cholesterol, blood pressure, and smoking were highly significant in all regions except Japan, where coronary deaths were too few for evaluation. Relative weight was not significant anywhere. Physical activity was significant only in southern Europe, where differences are associated with socioeconomic status. For all-causes death, age and blood pressure were highly significant risk factors in all regions as was smoking habit, except in Japan. Relative body weight tended to be a negative risk factor everywhere, significantly so in southern Europe. Expectations for coronary death from the experience in the United States and northern Europe greatly exceeded observed deaths in southern Europe for men of their age, serum cholesterol, blood pressure, smoking habits, physical activity, and relative weight. The reverse, prediction of coronary deaths in America and in northern Europe from the southern European experience, greatly underestimated the deaths observed. Similar cross-predictions between the United States and northern Europe were good for all-causes deaths, excellent for coronary deaths. Analysis of time trends in relationships of mortality to entry characteristics showed continued importance of age, blood pressure, and smoking and a tendency for the importance of cholesterol to fall in the last 5 years of follow-up.

Comparison of Multivariate Predictive Power of Major Risk Factors for Coronary Heart Diseases in Different Countries: Results from Eight Nations of the Seven Countries Study, 25-Year Follow-up

BACKGROUND It was hypothesized that among eight national groups of men aged 40-59 years enrolled in the Seven Countries Study, the multivariate coefficients of major risk factors predicting coronary heart disease mortality over 25 years would be relatively similar. MATERIALS AND METHODS Sixteen cohorts were located in eight nations and pooled, comprising one cohort in the USA, two in Finland, one in the Netherlands, three in Italy, two in Croatia (former Yugoslavia), three in Serbia (Yugoslavia), two in Greece and two in Japan, for a total of over 12000 subjects at entry. Coronary heart disease (CHD) mortality was defined as fatal myocardial infarction or sudden coronary death, and proportional hazard models were solved, for each country, with age, serum cholesterol level, systolic blood pressure and cigarette consumption as covariates. RESULTS The relationships between risk factors and CHD mortality were statistically significant for all risk factors and for all countries, except for age in Croatia and Japan, cholesterol in Croatia and Japan, systolic blood pressure in Serbia and Greece, and cigarette-smoking in the Netherlands, Croatia, Serbia and Greece. When comparing all pairs of coefficients (28 comparisons for each factor) significant differences were found on four occasions for age, on six occasions for cholesterol, on no occasion for blood pressure and on four occasions for cigarette-smoking. Other tests suggested a substantial homogeneity among multivariate coefficients. Estimates for pooled coefficients were: age, in years, 0.0570 (95% confidence limits 0.0465 and 0.0673); relative risk for 5 years 1.33 (95% confidence limits 1.26 and 1.40); serum cholesterol level in mg/dl, 0.0057 (95% confidence limits 0.0045 and 0.0069); relative risk for 40 mg/dl 1.31 (95% confidence limits 1.20 and 1.31); systolic blood pressure in mmHg, 0.0160, (95% confidence limits 0.0134 and 0.0185), relative risk for 20 mmHg 1.38 (95% confidence limits 1.31 and 1.45); cigarettes per day, 0.0220 (95% confidence limits 0.0170 and 0.0272); relative risk for 10 cigarettes per day 1.25 (95% confidence limits 1.18 and 1.31). CONCLUSIONS Great similarities were found in the multivariate coefficients of major coronary risk factors to CHD risk derived from population samples varying in CHD frequency.

Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study

Sixteen cohorts of men aged 40–59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12,763 subjects.Large differences in age-adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age-adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates.Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes in mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time.Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward.It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.

Seven Countries Study. First 20-Year Mortality Data in 12 Cohorts of Six Countries

Out of the original 16 cohorts in the Seven Countries Study on Cardiovascular Diseases, 12 population samples in six countries have reached the 20 year follow-up deadline. Data on mortality became fully available for a total of 8287 men aged 40-59 at entry examination (two cohorts in Finland, one in the Netherlands, three in Italy, two in Yugoslavia, two in Greece, and two in Japan). Death rates from CHD as well as from all causes follow the traditional falling north to south trend (18 fold between the extremes for CHD; 2.7 fold for total mortality). The differences in all causes mortality are, however, largely accounted for by the variation in CHD mortality. The mean entry levels of serum cholesterol and representative levels of the consumption of saturated fats, mono-unsaturated fats, poly-unsaturated fats and carbohydrates explain a large proportion of inter-cohort difference in CHD mortality (81% for saturated fats). By applying the proportional hazards model to the pools of national cohorts, with CHD deaths as end-point and five risk factors as covariates, only age and mean blood pressure are universally significant predictors of fatal events. Cholesterol, smoking habits, body mass index and physical activity play some part but not in all the pools. Age and mean blood pressure are also the only universal risk factors for all causes of death.

Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes.

BACKGROUND AND PURPOSE This report explores the prediction of long-term stroke mortality in cohorts of the Seven Countries Study. METHODS Sixteen cohorts of men aged 40 to 59 years at entry were examined at years 0, 5, and 10, with mortality follow-up through 25 years. RESULTS Stroke death rates in 25 years were high in rural Serbia, Croatia, and Japan; intermediate in Italy, Greece, and urban Serbia; and low in Finland, the Netherlands, and the United States. Age and blood pressure were powerful predictors of 25-year stroke mortality in almost all cohorts and countries. Proportional hazards regression coefficients were .0232 increase in stroke death hazard per millimeter of mercury (t=14.60) for systolic blood pressure and .0409 (t=13.41) for diastolic blood pressure. Moderate blood pressure increases from low usual levels were associated with lower stroke mortality rates in years 10 to 25. Increases of blood pressure starting from high usual levels were associated with increased rates of stroke mortality. Systolic blood pressure was associated with stroke mortality at given levels of diastolic pressure, but diastolic blood pressure was not predictive of stroke mortality at given levels of systolic blood pressure. CONCLUSIONS Associations of systolic and diastolic blood pressure with stroke mortality were similar in cultures with different stroke mortality rates. Increases in blood pressure were associated with subsequent excess stroke mortality only in those who started from high usual levels; this study finds lower stroke risk in those men whose blood pressure increased moderately from low usual levels. Diastolic blood pressure is not independently associated with stroke risk in these populations.

The role of a baseline casual blood pressure measurement and of blood pressure changes in middle age in prediction of cardiovascular and all-cause mortality occurring late in life: a cross-cultural comparison among the European cohorts of the Seven Countries Study.

Objective The first objective was to study the long-term association of a casual measurement of systolic blood pressure (SBP) with cardiovascular deaths (CVD) and all causes of death (ALL) occurring during 35 years of follow-up in different population samples of men aged 40–59 years in five European countries. The second objective was to study the predictive power of early change in SBP levels (years 0–10) in relation to late fatal events (years 10–35). Design, setting and participants A single measurement of SBP was considered in cohorts in Finland, The Netherlands, Italy, Serbia and Greece for a total of 6507 men. Three partitioned proportional hazards models were solved, one for each independent and subsequent time block of 10 years, after excluding data from the first 5 years, to predict the risk of cardiovascular disease deaths of atherosclerotic origin (CVD) and all cause mortality (ALL). Independently, the predictive power of SBP changes (Δ-SBP) occurred during the first 10 years of follow-up was explored as a possible additional risk factor in relation to CVD and ALL deaths occurring between year 10 and year 35 of follow-up. Results Partitioned hazard scores derived from the three partitioned functions were cumulated. The resulting curves showed a continuous and significant association of baseline SBP with CVD and ALL deaths during three decades, although the strength of association declined significantly from the first to the third decade. The relative risk for 20 mmHg of SBP (and its 95% confidence intervals) in predicting CVD deaths was 1.65 (1.54–1.77) for the first 10-year block; 1.33 (1.24–1.42) for the second block; and 1.22 (1.13–1.31) for the last 10-year block. The corresponding levels of ALL deaths were 1.41 (1.34–1.49), 1.26 (1.19–1.32) and 1.11 (1.05–1.17). Changes in SBP during 10 years (Δ-SBP) added predictive power to baseline measurements in a direct and significant way, with a relative risk for a change of 10 mmHg of 1.14 (1.10–1.17) for CVD deaths and 1.11 (1.09–1.13) for ALL deaths. Conclusion A single measurement of systolic blood pressure in middle-aged men maintains a strong relationship with fatal CVD and ALL deaths during the next 35 years, although for late events the strength of the association definitely declines. Changes in systolic blood pressure levels during the first 10 years of follow-up add predictive power, while baseline measurements retain their predictive power.

Integrated evaluation of relation between coronary lesion features and stress echocardiography results: the importance of coronary lesion morphology

OBJECTIVES The aim of this study was to analyze, in the same group of patients, the relationship between multiple variables of coronary lesion and results of exercise, dobutamine and dipyridamole stress echocardiography tests. BACKGROUND Integrated evaluation of the relation between stress echocardiography results and angiographic variables should include not only the assessment of stenosis severity but also evaluation of other quantitative and qualitative features of coronary stenosis. METHODS Study population consisted of 168 (138 male, 30 female, mean age 51+/-9 years) patients, on whom exercise (Bruce treadmill protocol), dobutamine (up to 40 mcg/kg/min) and dipyridamole (0.84 mg/kg over 10 min) stress echocardiography tests were performed. Stress echocardiography test was considered positive for myocardial ischemia when a new wall motion abnormality was observed. One-vessel coronary stenosis ranging from mild stenosis to complete obstruction of the vessel was present in 153 patients, and 15 patients had normal coronary arteries. The observed angiographic variables included particular coronary vessel, stenosis location, the presence of collaterals, plaque morphology according to Ambrose classification, percent diameter stenosis and obstruction diameter as assessed by quantitative coronary arteriography. RESULTS Covariates significantly associated with the results of physical and pharmacological stress tests included for all three stress modalities presence of collateral circulation, percent diameter stenosis and obstruction diameter, as well as lesion morphology (p < 0.05 for all, except collaterals for dobutamine stress test, p = 0.06). By stepwise multiple logistic regression analysis, the strongest predictor of the outcome of exercise echocardiography test was only percent diameter stenosis (p = 0.0002). However, both dobutamine and particularly dipyridamole stress echocardiography results were associated not only with stenosis severity - percent diameter stenosis (dobutamine, p = 0.04; dipyridamole, p = 0.003) - but also, and even more strongly, with lesion morphology (dobutamine, p = 0.006; dipyridamole, p = 0.0009). As all of stress echocardiography results were significantly associated with percent diameter stenosis, the best angiographic cutoff in relation to the results of stress echocardiography test was: exercise, 54%; dobutamine, 58% and dipyridamole, 60% (p < 0.05 vs. exercise). CONCLUSIONS Integrated evaluation of angiographic variables have shown that the results of dobutamine and dipyridamole stress echocardiography are not only influenced by stenosis severity but also, and even more importantly, by plaque morphology. The results of exercise stress echocardiography, although separately influenced by plaque morphology, are predominantly influenced by stenosis severity, due to a stronger exercise capacity in provoking myocardial ischemia in milder forms of coronary stenosis.

Homogeneity in the relationship of serum cholesterol to coronary deaths across different cultures: 40-year follow-up of the Seven Countries Study

Background The aim was to investigate whether multivariate coefficients of serum cholesterol in the prediction of coronary heart disease (CHD) deaths were similar across different cultures in a long-term follow-up. Design Thirteen cohorts for a total of 10157 men aged 40–59 years at entry, enrolled in seven countries (USA, Finland, the Netherlands, Italy, Serbia, Greece, Japan) were repeatedly examined and followed up for 40 years. Methods Serum cholesterol measured at baseline, and then on repeated occasions, was studied, using multivariate models, in relation with the occurrence of CHD deaths during a 40-year follow-up. Results Homogeneity of multivariate serum cholesterol coefficients was found considering cholesterol levels at baseline, as average of up to three measurements during the first 10 years, as average of up to six measurements in 35 years, using the time-dependent technique with up to three measurements in 10 years, and with up to six measurement in 35 years. Conclusion The strength of the association between serum cholesterol and CHD death seems homogeneous across different cultures characterized by different levels of serum cholesterol and different absolute risk of CHD death. Eur J Cardiovasc Prev Rehabil 15:719–725

Long-term trends in major cardiovascular risk factors in cohorts of aging men in the European cohorts of the Seven Countries Study

Background and aims: Time trends in major cardiovascular risk factors are described in cohorts of middle-aged men followed for 35 years in 9 European cohorts of Finland, The Netherlands, Italy, Serbia and Greece. Methods: Men aged 40 to 59 years at entry in the early 1960s were repeatedly re-examined 3 to 5 times over the last 35 years. Systolic blood pressure, serum cholesterol, body weight and body mass index were considered for analysis, including study of aging (35 years of follow-up) and of generation effects (10 years for men aged 50–59 in the period 1960–1970 and separately 10 years for men aged 75–84 years in the period 1985–1995). Results: For the aging effect, average systolic blood pressure increased approximately 15 mmHg over 25 years maintaining a steady state thereafter, the largest increases being found in Serbia and Greece. Average serum cholesterol varied between approximately 4.5 in Serbia and 6.5 mmol/L in Finland in about 1960. Twenty-five years later, the average level was about 6 mmol/L in all five countries and decreased slightly thereafter. Average body weight and body mass index increased in all countries for 25 years and levelled off thereafter. For the generation effect, average systolic blood pressure decreased in all countries, with the exception of men aged 50–59 in Serbia and men aged 75–84 in The Netherlands. Average serum cholesterol uniformly increased in men aged 50–59 for the younger age-class and slightly decreased in men aged 75–84. Average body weight and body mass index increased systematically in all countries and in both age groups. Conclusions: Major changes were the great increases in average systolic blood pressure and serum cholesterol level in Serbia and in systolic blood pressure level in Greece between 1960 and 1985, and the large decrease in average serum cholesterol in Finland between 1970 and 1995. Average body weight and body mass index showed universal increases in both middle-aged and older men after 1960.

Efficiency of Ergonovine Echocardiography in Detecting Angiographically Assessed Coronary Vasospasm

C vasospasm plays a major role in provoking myocardial ischemia in patients with variant angina, but also in some patients with acute coronary syndrome including unstable angina, myocardial infarction, and sudden death. Ergonovine provocation has been used for 20 years for detection of coronary artery spasm. Most data on ergonovine testing have been reported in the preselected group of patients with variant angina, establishing ergonovine as a test of high diagnostic confidence. In current clinical practice, when a marked decline in the use of ergonovine testing in the catheterization laboratory is observed, accompanied by promising reports on ergonovine echocardiography, a question remains on the incidence, safety, and usefulness of provocative testing for coronary vasospasm in patients with chest pain syndrome and nonsignificant coronary artery stenosis. Thus, the objectives of our study were to evaluate (1) the incidence of angiographically assessed coronary vasospasm in a consecutive population of patients with nonsignificant coronary artery disease, (2) the efficiency of simultaneously performed ergonovine echocardiography in identifying coronary vasospasm, and (3) the relation between ergonovine echocardiographic and angiographic results. • • • The vasomotor response to ergonovine was studied in 100 consecutive patients (45 men and 55 women, mean age 52 8 years) with chest pain syndrome and hemodynamically nonsignificant coronary stenosis (diameter stenosis, mean 26 10%). No patient had previous myocardial infarction, congestive heart failure, severe congenital or valvular heart disease, or documented cardiomyopathy. Patients with severe hypertension (systolic pressure 180 mm Hg and diastolic pressure 110 mm Hg), recent malignant ventricular arrhythmia, or conduction abnormalities were not considered for the study. All drug medications were stopped 48 hours before testing, except angiotensin-converting enzyme inhibitors and short-acting nitrates. Our institution’s human use committee approved the study, and all patients gave informed consent. According to predominant clinical symptoms, patients were classified into the following categories: chest pain during rest (n 18), chest pain during effort and rest (n 10), nocturnal chest pain (n 9), chest pain in the cold (n 19), and chest pain during stressful situations (n 44). The pretest probability of having coronary artery disease was 60 15%. In 84 patients, submaximal Bruce treadmill, exercise stress electrocardiographic testing was performed before diagnostic angiography; in 16 patients exercise testing was not performed because of poor patient motivation or physical inability to perform adequate exercise tests. No patient developed significant ST-segment changes during and after stress testing, defined as a decrease or increase in ST segment of 0.1 mV 0.08 second after the J point, or rhythm and conduction abnormalities. The ergonovine test was performed in consecutive patients at the end of diagnostic catheterization showing nonsignificant coronary artery stenosis and a normal left ventriculogram. All patients underwent selective coronary angiography using the Judkins technique, and multiple views of each coronary artery were obtained. Angiographic evaluation during ergonovine testing was performed in the view that best showed the coronary lesion. Doses of 0.05, 0.10, and 0.20 mg of ergonovine maleate (total cumulative dose 0.35 mg) were given intravenously in succession at 3-minute intervals, followed by intracoronary injection of nitroglycerin. Angiography was performed before the study, at the end of each stage, and after administration of nitroglycerin. Systemic blood pressure, electrocardiography, and echocardiography for wall motion changes were monitored continuously and recorded at the end of each stage. Electrocardiography was considered positive for myocardial ischemia when 0.1 mV elevation or depression of the ST segment was found 0.08 second after the J point. Coronary arteriographic images were digitized and analyzed (off-line) with the quantitative coronary angiography imaging system (Medis CMS software, version 1.11, Nuenen, The Netherlands) by an observer unaware of patient clinical data and echocardiographic results. After visual inspection of the coronary artery, the frame of optimal clarity in the end-diastolic part of From the University Institute for Cardiovascular Diseases, Department for Diagnostic and Catheterization Laboratories, Clinical Center of Serbia, Belgrade, Yugoslavia. Dr. Ostojic’s address is: University Institute for Cardiovascular Diseases, Department for Diagnostic and Catheterization Laboratories, Clinical Center of Serbia, 8 Koste Todorovica, Belgrade, Yugoslavia. E-mail: miodrag.ostojic@kcs.ac.yu. Manuscript received March 16, 2001; revised manuscript received and accepted July 3, 2001.